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Endothelial Cell Injury in Atherosclerosis Is Regulated by Glycolysis (Review)

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Endothelial Cell Injury in Atherosclerosis Is Regulated by Glycolysis (Review) INTERNATIONAL JOURNAL OF MOleCular meDICine 47: 65-76, 2021 Mechanism overview and target mining of atherosclerosis: Endothelial cell injury in atherosclerosis is regulated by glycolysis (Review) RUIYING WANG1-5, MIN WANG1-5, JINGXUE YE1-5, GUIBO SUN1-5 and XIAOBO SUN1-5 1Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences; 2Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences; 3Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences; 4Key Laboratory of Efficacy Evaluation of Chinese Medicine Against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences; 5Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine Prescription, Chinese Academy of Medical Sciences, Beijing 100193, P.R. China Received August 14, 2020; Accepted November 5, 2020 DOI: 10.3892/ijmm.2020.4798 Abstract. Atherosclerosis (AS) is a chronic disease with a In conclusion, endothelial cell injury in AS may be alleviated by complex pathology that may lead to several cardiovascular and glycolysis and is a potential clinical treatment strategy for AS. cerebrovascular diseases; however, further research is neces- sary to fully elucidate its pathogenesis. The main risk factors for AS include lipid metabolism disorders, endothelial cell Contents injury, inflammation and immune dysfunction, among which vascular endothelial cell damage is considered as the main 1. Introduction trigger for AS occurrence and development. Endothelial cell 2. Factors implicated in AS damage leads to enhanced intimal permeability and leukocyte 3. Vascular endothelial cells adhesion, promoting thrombus formation and accelerating 4. Glycolysis disease progression. The function of endothelial cells is 5. Prediction and analysis of targets associated with endothelial affected by glycolysis regulation, since 80% of ATP in these cell glycolysis in AS cells is produced via this pathway. Genes associated with AS 6. Discussion and endothelial cell glycolysis, including AKT1, interleukin-6, vascular endothelial growth factor A, TP53, signal transducer and activator of transcription 3, SRC and mitogen-activated 1. Introduction protein kinase 1, were screened. Through integrated analysis, these genes were found to play a key role in AS by regulating Atherosclerosis (AS) is a chronic disease with complex multiple signaling pathways associated with cell signal trans- etiology, which involves early local injury of the arterial duction, energy metabolism, immune function and thrombosis. intima, followed by lipid deposition, proliferation of the intimal fibrous tissue, local thickening of the intima and, ultimately, plaque formation (1). Vascular plaque-induced stenosis by AS may lead to insufficient arterial blood supply and cardiovas- cular diseases (2). The most serious complications caused by Correspondence to: Professor Guibo Sun or Professor Xiaobo Sun, plaque rupture are myocardial infarction, cerebral ischemia, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, 151 Malianwa and ischemia of the surrounding tissue (3). The pathogenesis North Road, Haidian, Beijing 100193, P.R. China of AS has not been fully elucidated to date. Previous studies E-mail: [email protected] have demonstrated that AS is associated with lipid metabolism E-mail: [email protected] disorders, endothelial cell damage, inflammation and immune dysfunction, involving macrophages, endothelial cells, Key words: endothelial injury, atherosclerosis, glycolysis, target, vascular smooth muscle cells and platelets (4,5). In recent mechanism years, AS animal models mainly include mice, rabbits, minia- ture pigs, non-human primates and transgenic animals (6). AS is a vicious circle combining multiple factors and long-term 66 WANG et al: ROLE OF ENDOTHELIAL GLYCOLYSIS IN ATHEROSCLEROSIS effects. So, elucidating the underlying mechanism is crucial endothelial cell function, and causing increased permeability for the treatment and prevention of the disease. and lipid deposition in the inner membrane (20). Ox-LDL Despite not having been fully elucidated, it is believed that exhibits strong affinity for scavenger receptors found on lipid metabolism disorders, endothelial cell injury, inflamma- mononuclear macrophages, leading to its quick internalisa- tion and immune dysfunction are the most important factors tion (21). However, Ox-LDL is toxic for macrophages, causing implicated in the pathogenesis of AS (5,7). Functional damage them to become activated, rapidly proliferate, aggregate and of endothelial cells is the initiating step in the early stage of degenerate (22). Finally, the macrophages undergo apoptosis AS (8). Endothelial cell damage in AS plaques leads to further and become foam cells, which then aggregate to form AS lipid plaque instability, rupture (9) and secondary thrombosis, thus plaques. Moreover, Ox-LDL binds to vascular endothelial cells accelerating disease progression and affirming the important through lectin-like oxidized LDL receptor-1 to disrupt intra- role of endothelial cell integrity (10). Glycolysis, the most cellular signaling and cause endothelial cell dysfunction (23). important energy source for endothelial cells, is used to quickly Ox-LDL can also promote the continuous proliferation of produce energy, enabling cells to respond to environmental vascular smooth muscle cells and their outward migration to changes (11). Intermediate metabolic products produced form plaques on the inner wall of blood vessels. during glycolysis affect cell survival (12); therefore, glycolytic rates in endothelial cells play a key role in maintaining their Role of endothelial cell injury in AS. Disruption of endothelial homeostasis and reducing the risk for AS. cell morphology and function leads to vascular barrier function The aim of the present study was to review the pathogenesis impairment, as well as to changes in the intimal integrity and of AS, the role of endothelial cell damage and glycolysis, and permeability (24). The apoptosis and shedding of endothelial the role of associated target genes and the involved signalling cells promote the adhesion and aggregation of platelets from pathways, in order to indicate new approaches to the research the blood (25). Dysfunctional endothelial cells, macrophages on AS pathogenesis and intervention methods, and aid in the and platelets secrete a variety of growth factors and vasoactive development of novel treatments for AS. substances, stimulating the continuous proliferation of smooth muscle cells in the media, and enter the intima, while also 2. Factors implicated in AS causing contractions of the vascular wall (26). As a result, the fatty plaques increase in size while the lumen becomes progres- Pathogenesis. The pathogenesis of AS is extremely compli- sively narrowed, promoting the formation of AS lesions (8). cated (Fig. 1). AS is currently considered to be the result of the interaction among various mechanisms, including lipid metab- Role of inflammation in AS.AS involves not only lipid deposi- olism disorder, inflammatory cell infiltration, oxidative stress, tion in blood vessel walls, but also chronic inflammation (27). immune dysfunction and vascular endothelial cell damage, the Oxidative stress persists throughout AS. AS has been proven latter of which ultimately leads to plaque rupture and throm- to be a chronic inflammatory disease initiated in the arterial bosis, leading to serious cardiovascular and cerebrovascular wall, mainly driven by modification of endogenous structures diseases (1,4,13). and dysfunction of the vascular endothelium (28). Certain lipids act as signaling molecules, and bind to cell receptors Role of oxidative stress in AS. Oxidative stress is the initi- to activate the expression of specific genes and produce a ating factor of AS inflammatory response, with reactive number of pro-inflammatory cytokines (19). This leads to oxygen species (ROS) and oxidized low-density lipoprotein an increase in the numbers of inflammatory cells, including (Ox‑LDL; formed by oxidative modification of LDL) being the macrophages, increased phagocytosis of Ox-LDL and produc- main factors responsible for endothelial cell damage and for tion of pro-inflammatory factors, such as tumor necrosis inducing the expression of pro‑inflammatory factors in endo- factor (TNF)-α, interleukin (IL)-1 and IL-8 (29). These factors thelial cells (14,15). When endothelial cells are continuously further aggravate the pathology of AS. exposed to external as well as endogenous oxidants, oxidative stress is likely to induce production of various biologically Role of immune dysfunction in AS. AS is also an autoim- active substances, which may cause endothelial cell func- mune disease, stimulated by accumulated lipoproteins, as tional damage and apoptosis (16,17). This process leads to the well as specific T lymphocytes and their antibodies, in the synthesis and release of inflammatory factors, further aggra- blood vessel wall (30). It was previously demonstrated
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